PAR-03-099: CANCER PROGNOSIS AND PREDICTION: SBIR/STTR INITIATIVE

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CANCER PROGNOSIS AND PREDICTION: SBIR/STTR INITIATIVE RELEASE DATE: April 8, 2003 PA NUMBER: PAR-03-099 EXPIRATION DATE: December 12, 2003, unless reissued National Cancer Institute (NCI) (http://www.nci.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.394 LETTER OF INTENT RECEIPT DATES: May 14, 2003 and November 13, 2003 APPLICATION RECEIPT DATES: June 11, 2003 and December 11, 2003 This Program Announcement (PAR) replaces PAR-01-062, which was published in the NIH Guide on March 1, 2001. NOTICE: This program announcement (PAR) must be read in conjunction with the current Omnibus Solicitation of the National Institutes of Health, Centers for Disease Control and Prevention, and Food and Drug Administration for Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Grant Applications. The solicitation (see http://grants.nih.gov/grants/funding/sbirsttr1/index.pdf) contains information about the SBIR and STTR programs, regulations governing the programs, and instructional information for submission. All instructions within the Omnibus Solicitation apply with the following exceptions: o special receipt dates and mailing instructions o initial review convened by the NCI Division of Extramural Activities o additional review considerations o more flexible time and budget specifications o special provision for competitive renewal of certain R44 or R42 awards o special provision for competitive supplements to support extended development studies, including clinical trials THIS PAR CONTAINS THE FOLLOWING INFORMATION o Purpose of the PAR o Research Objectives o Mechanisms of Support o Project Period and Amount of Award o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Receipt and Review Schedule o Required Federal Citations PURPOSE OF THIS PAR The Cancer Diagnosis Program of the National Cancer Institute invites small business applications for research projects to evaluate the utility and pilot the application of new strategies for determining prognosis or predicting response to therapy. This will provide tools to improve clinical decision- making in the care of cancer patients. This program is intended to accelerate the translation of new discoveries into clinical practice by enabling investigators to apply new diagnostic strategies to clinical problems. The primary objective is to move research quickly and directly from the promising exploratory stage through further assay development into initial confirmatory testing in a clinical setting. This PAR will utilize the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms, but will be run in parallel with a program of identical scientific scope, (http://grants.nih.gov/grants/guide/pa-files/PAR-03-098.html), that will utilize the Phased Innovation Award (R21/R33) mechanism. Applicants are strongly encouraged to read both announcements. RESEARCH OBJECTIVES Background The number of clinical laboratory assays currently in routine use in oncology is very small. For example, estrogen and progesterone receptor status of breast cancers is used to predict response to hormonal therapy. Blood levels of prostate specific antigen and human chorionic gonadotropin in prostate cancer and germ cell cancer, respectively, are used to assess the effectiveness of treatment and to detect recurrence. Patients whose tumor cells exhibit over-expression or amplification of the Her-2/neu gene may be offered trastuzumab, forerunner of a new class of therapeutic agents directed against specific molecular targets. These markers are the exception, not the rule. During the part five years the College of American Pathologists, ASCO Expert Panels and the American Joint Committee on Cancer have carefully considered many new markers proposed for use in managing breast, colon and prostate cancer, but have found none with proven clinical utility sufficient to justify their adoption for routine practice. Recently the NCI has sought to encourage the rapid appraisal of new candidate prognostic and predictive markers through a series of program announcements soliciting exploratory (R21) studies. An increasing number of publications have described new molecules, new patterns of gene expression and new aspects of tumor cell growth that appear to be correlated with known prognostic factors. However, very few markers progress beyond the stage of an initial promising result. Studies to move the development of a new diagnostic test beyond the exploratory stage require large numbers of patient samples with associated clinical data, a robust, efficient assay format and substantial clinical input. The transition from an exploratory marker study to initial confirmatory testing in a clinical setting may involve additional developmental work. For example, the study design may change from a retrospective to a prospective analysis or from a single institution to a multi-institutional setting. Frequently an assay format must be modified, which may require the generation and characterization of additional reagents. Procedures for standardization between collaborating laboratories may be needed. Research Goals and Scope This program is intended to support projects that test the value of new strategies for predicting the course of the disease or the response to therapy as tools in clinical decision-making. The desired outcome will be studies with sufficient statistical power using efficient assay techniques that are conclusive enough to support the initiation of larger clinical trials designed to influence practice recommendations or to pursue FDA approval of a new device or analytic reagent. Partnerships of appropriate medical institutions with biotechnology companies and medical device manufacturers are encouraged. Phase I applications will be considered exploratory, so that extensive preliminary data from the applicant's own laboratory are not required. However, the project must be based on a strong rationale, and the applicant should provide evidence that the initial clinical evaluation of the proposed diagnostic strategy is promising. Applicants should justify their proposals on the strength of the clinical study proposed for a future Phase II project; the Phase I award provides time for necessary preliminary work such as, for example, the substantial modification of an assay format. Phase II projects must be described in sufficient detail to permit reviewers to assess the significance and innovation of the proposed work and the strength of the experimental design. All applicants are expected to provide promising evidence of clinical utility for their proposed diagnostic strategy and to show how their new test or procedure will aid the process of clinical decision-making for a specific group of patients. The application should clearly state the clinical question that the new test or procedure is intended to address: for example, diagnosis, prognosis, prediction of response to therapy, disease monitoring, etc. Investigators should plan to report correlations between the new diagnostic test and other measures used in the same clinical setting, and they should describe what additional information beyond standard clinical parameters that the new test is expected to provide. Investigators who propose prospective studies must clearly describe the arrangements for collection and analysis of patient outcome data, especially if follow-up will be required beyond the end of the award period. Proposals will be evaluated on the strength of the scientific rationale, the significance of the problem to be addressed, the adequacy of the proposed statistical design, the feasibility of accrual of study participants or human tissue specimens and the choice of assay format and analytic performance criteria. Applicants for FAST-TRACK (combined Phase I/II) projects need to provide information in the application or to propose milestones that will demonstrate the feasibility of the Phase II project. Milestones must be designed to permit a straightforward decision as to whether or not the applicant is ready to initiate Phase II. Milestones should also be provided to show that the assay format to be used in Phase II meets necessary performance standards for sensitivity, specificity and reproducibility. For example, milestones could be used to demonstrate the feasibility of the Phase II project in the following ways: o Establish assay conditions: types of specimens, fixation processes, antigen retrieval methods, reagents and other components of the assay system, detection system, positive and negative controls, etc. o Define procedures for scoring and for reporting data. o Demonstrate that the assay or test system proposed for use in the R33 phase has the required sensitivity, specificity and reproducibility. o Establish procedures for standardization and demonstrate that comparable results can be obtained from assays performed at multiple sites. o Estimate the prevalence of the marker on a pilot set of specimens of the same type (fixed, frozen, etc.) and the same patient characteristics as the set proposed for the R33 study. o Provide evidence that the number of participants or specimens required by the study design in the R33 phase can be accrued. This list is intended for illustration, and is not meant to prescribe or to limit the milestones an application may include. See below (SUBMITTING AN APPLICATION) for examples. MECHANISMS OF SUPPORT This PAR uses the SBIR and STTR mechanisms, which are set aside programs. This PAR is a one-time announcement that may be reissued. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Future unsolicited, competing-continuation applications based on this project will compete with all SBIR/STTR applications and will be reviewed according to the customary peer review procedures. This PAR uses just-in-time concepts. For this PAR, the modular budgeting format will not be used. Except as otherwise stated in this PAR, awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, March 2001, available at: http://grants.nih.gov/grants/policy/nihgps_2001/, or as revised. The SBIR/STTR mechanism requires that the intent of the research be the commercialization of a product or service. Applications can be submitted for support as Phase I STTR (R41) or Phase I SBIR (R43) grants; Phase II STTR (R42) or Phase II SBIR (R44) grants; or the SBIR/STTR FAST-TRACK option as described in the Omnibus Solicitation. Phase II applications in response to this PAR will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The Phase II application must be a logical extension of the Phase I research but not necessarily a Phase I project supported in response to this PAR. PROJECT PERIOD AND AMOUNT OF AWARD The Omnibus Solicitation indicates the statutory guidelines of funding support and project duration periods for SBIR and STTR Phase I and Phase II awards. However, some projects are likely to require longer time periods and/or larger budgets to accomplish the proposed aims. Therefore, if adequately justified, for this PAR budgets up to $100,000 direct costs per year and time periods up to 2 years for Phase I can be requested. Phase II applications submitted in response to this PAR have no budget limitations and may request up to four years of support. For FAST-TRACK applications the total duration of Phase I plus Phase II cannot exceed 5 years. This PAR encourages projects with aims focusing on clinical evaluation of new diagnostic strategies. Accomplishing these aims may require expertise not present in the applicant small business, and a sub-contract site within the award may be required. Costs for this research may exceed the normal expectations for percent of the total grant budget allocated to subcontracts described in the Omnibus Solicitation. If adequately justified, for this PAR applications may exceed this guideline. Resources provided for such research activity will be limited for that activity and cannot be rebudgeted. ELIGIBLE INSTITUTIONS Eligibility requirements are described in the SBIR/STTR Omnibus Solicitation. Only small business concerns are eligible to submit applications. A small business concern is one that, on the date of award for both Phase I and Phase II agreements, meets ALL of the criteria as described in the SBIR/STTR Omnibus Solicitation. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. On an SBIR application, the principal investigator must have his/her primary employment (more than 50%) with the small business at the time of award and for the duration of the project. The PI on an STTR application may be employed with the small business concern or the participating non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant small business concern, which is characterized by an official relationship between the small business concern and that individual. SPECIAL REQUIREMENTS An annual meeting of all investigators funded through this program will be held to share results and research insights that may further progress in the program. Applicants should request travel funds in their budgets for the principal investigator and one additional senior investigator to attend this annual meeting. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PAR and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Tracy G. Lugo, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: 301-402-7819 Email: lugot@mail.nih.gov (for general inquiries and for projects specifically related to breast cancer, gynecologic cancers, gastric cancer, pancreatic cancer or brain tumors) Magdalena Thurin, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: 301-402-7819 Email: thurinm@mail.nih.gov (for projects related to colon cancer, skin cancers including melanoma, sarcomas, or acute leukemias) James V. Tricoli, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: 301-402-7819 Email: tricolij@mail.nih.gov (for projects related to prostate cancer, renal or bladder cancer, liver cancer, lymphomas or chronic leukemias) Barbara Conley, M.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Telephone: (301) 496-1591 FAX: 301-402-7819 Email: conleyb@mail.nih.gov (for projects related to lung cancer, head and neck cancer or esophageal cancer) o Direct your questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: ncirefof@dea.nci.nih.gov o Direct your questions about financial or grants management matters to: Mr. Shane Woodward Grants Administration Branch Office of Management National Cancer Institute 6120 Executive Blvd. Room EPS 243 Bethesda, MD 20892 Phone: 301-496-8649 Fax: 301-496-8601 e-mail: woodwars@mail.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this PAR Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Tracy G. Lugo, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Blvd., Room EPN 6035A Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-1591 FAX: 301-402-7819 Email: lugot@mail.nih.gov SUBMITTING AN APPLICATION The PHS 398 research grant application must be used for all SBIR/STTR Phase I, Phase II and FAST-TRACK applications (new and revised.) The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Prepare your application in accordance with the SBIR/STTR Omnibus Solicitation and the PHS 398. Helpful information on the preparation of the application can be obtained at: http://grants.nih.gov/grants/funding/sbirgrantsmanship.pdf. The NIH will return applications that are not submitted using the PHS 398 grant application. For further assistance contact GrantsInfo, Telephone: (301) 710-0267, Email: GrantsInfo@mail.nih.gov The title and number of this PAR must be typed on line 2 of the face page of the application. NIH will treat as confidential any scientific, pre-clinical, or clinical data that the applicant deems to be proprietary and confidential. Applicants are encouraged to include all information required for adequate evaluation by reviewers. However, in the event that assays and technology are not yet patent protected and the applicant does not wish to include complete details, the application should at a minimum provide a demonstration (results) of the capabilities of the proposed approach. PHASE I: Demonstration of feasibility of the innovative approach. Research should be proposed to provide sufficient reason to continue the assay development in Phase II. If two years of support are requested, the goals for the first year should be clearly stated and not simply a reiteration of specific aims. The second year of the Phase I budget should be included and clearly identified on the Budget Justification page, using categorical totals if costs deviate significantly from the first year of the budget, with narrative justifications for the increase(s). If the second year simply escalates due to cost of living factors, a statement to that effect with the escalation factor should be included rather than categorical totals. The cost for the first year must be entered on box 7 and the cost for the entire project period must be entered in box 8 on the Face Page of the application. Support for the second year will be contingent upon Institute programmatic evaluation to ensure that investigators are accomplishing the goals presented. PHASE II: Development of approach to a stage at which the assay or procedure can be tested in a clinical setting. Goals for each year of support should be clearly presented. Support for years two to four, if requested, is dependent upon Institute programmatic review of progress and achievement of the proposed goals. For example, if a goal such as timely accrual of study participants is not achieved, the continuation years may not be supported. Item d of the Research Plan should include a statistical section that discusses the choice of the study design and laboratory methods. Sample sizes must be clearly stated and justified with power calculations. The statistician involved with the project should be identified and a letter of support included if no effort is requested in the budget. Plans for data management and verification of clinical research data should also be described. Collaborative arrangements should be clearly documented, and where collaborations involve NCI-sponsored clinical trials the protocol numbers should be provided. Letters of support should be included in the application to substantiate plans for collection of follow-up information beyond the period of award. Where appropriate, applicants are strongly encouraged to include a copy of the complete clinical protocol in the Appendix. See "REQUIRED FEDERAL CITATIONS" below for further requirements for data and safety monitoring requirements for NCI-supported clinical trials. FAST-TRACK: Applications may be submitted for combined Phase I and Phase II, FAST- TRACK consideration as described in the Omnibus Solicitation. Phase I, FAST-TRACK applications must specify clear, measurable milestones that should be achieved prior to Phase II funding. Failure to provide such information in the Phase I application may be sufficient reason for the peer review committee to exclude the Phase II from consideration. If so, the applicant may apply later for Phase II support. Such applications will be reviewed by an appropriate scientific review group convened by the NIH. The following examples are provided to illustrate the recommended level of detail for milestones, but should not be considered an exhaustive list of potentially appropriate milestones. Nor is this list intended to recommend the use of specific statistical tests. You should apply those methods that are most appropriate for your data. o Assay conditions will be optimized to achieve conditions where the analytic sensitivity is at least X and the specificity is at least Y when Z samples, half of which are truly positive for the analyte, are studied. o The assay to be used in the R33 phase will perform reproducibly as defined by a coefficient of variation less than Y in a series of X test specimens. o Show that the marker, as defined by a cut-off value of X, is correlated with the outcome of interest in the patient population for the R33 phase by demonstrating that there is a difference of at least Y% in the prevalence of the marker when comparing N1 patients with outcome type 1 to N2 patients with outcome type 2. o The prognostic significance of molecular profiles defined in the training set will be demonstrated in an independent set of X specimens. This milestone will be met if values of Y% or higher are achieved for both sensitivity and specificity in predicting the clinical outcome of interest for the R33 phase. Special provisions described in this PAR pertaining to Phase I and Phase II also apply to FAST- TRACK applications. COMPETING CONTINUATION PHASE II APPLICATIONS: A competitive renewal of Phase II for up to an additional three years be requested for current Phase II awards which have successfully developed cancer diagnostic tests that should be considered for testing in a clinical trial. Research activities supported by the competing continuation award would be expected to include steps required to seek FDA approval. All Phase II provisions stated in this PAR apply to the Phase II competitive renewal application. COMPETING SUPPLEMENTS: A competing supplemental application may be submitted at the receipt dates presented on page 1 of this PAR to request support for a significant expansion of an existing project's scope, research protocol or to add new specific aims. The time requested for support may not extend beyond the term of the existing award, but new aims supported by a supplement may be included in an application for a competitive renewal of an eligible Phase II award (see above). Phase II awardees who wish to add research aims to obtain data required for PMA or IDE filing or to conduct clinical trials are encouraged to apply for supplemental funding. Instructions for application can be found in the PHS 398 instructions, Chapter VI, Section 9, Research Plan. Awardees should consult with the Program Director prior to submission of the supplement request. ADMINISTRATIVE SUPPLEMENTS: Supplements to extend a peer-reviewed and funded specific aim for reasons that were unpredicted at the time of application can be requested at any time. New aims to the award cannot be added with this process. Examples appropriate for this PAR would be, but are not limited to, requirements for additional studies requested by the FDA as part of the regulatory approval process that were not included in the original research plan. Administrative supplement requests should be discussed with and submitted to the Program Director. Potential applicants are encouraged to contact program staff for guidance and to read the advice and information on the web sites. However, responsibility for planning, direction, and execution of the proposed research will be solely that of the applicant. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Rockville, MD 20852 (for express/courier service) APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (http://grants.nih.gov/grants/guide/notice-files /NOT-CA-02-002.html) This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. RECEIPT OF APPLICATIONS: Applications must be received by or mailed before the receipt dates described on the first page of this program announcement. The CSR will not accept any application in response to this PAR that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Upon receipt, applications will be reviewed by CSR staff for completeness and by NCI program staff for adherence to guidelines. Incomplete applications and applications not adhering to instructions described above will be returned to the applicant without further review. Applications that are complete and adhere to the guidelines of this PAR will be evaluated for scientific and technical merit and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of this PAR by an appropriate peer review group convened by the NCI, Division of Extramural Activities, in accordance with the peer review criteria listed below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Those that receive a priority score will undergo a second level review by the National Cancer Advisory Board. REVIEW CRITERIA The goals of NIH-sponsored research are to advance our understanding of biological systems, improve the control of disease, and enhance health. Within this framework, the specific goals of this PAR include the development and testing of new strategies for cancer diagnosis in clinical settings by SBIR/STTR awardees. In the written comments, the reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment ALL SBIR/STTR APPLICATIONS: 1. Significance: Does the study address an important problem? Does the proposed project have commercial potential to lead to a marketable product or process? What may be the anticipated commercial and societal benefits of the proposed activity? If the aims of the application are achieved, how do they advance scientific knowledge? Does the proposal lead to enabling technologies (instrumentation, software, etc.) for further discoveries? What is the throughput and cost effectiveness of the proposed assay(s)? Will the technology have a competitive advantage over existing/alternative technologies that can meet the market needs? What will be the impact on future clinical trials or on clinical practice? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? This includes the statistical rationale for the study design and the choice of sample size. Is the proposed plan a sound approach for establishing technical and commercial feasibility? Does the applicant acknowledge potential problem areas and consider alternative strategies? Has the applicant considered how the Phase II study, if promising, could proceed into eventual definitive testing of the diagnostic strategy? 3. Innovation: Does the project challenge existing paradigms or employ novel technologies, approaches, or methods? Are the aims original and innovative? How is the proposed diagnostic strategy superior to existing alternatives? What additional uses can be projected for the proposed assay(s), or what additional groups of patients might benefit from the new diagnostics strategy? 4. Investigator: Is the Principal Investigator capable of coordinating and managing the proposed SBIR/STTR? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers including consultants and sub-contractors (if any)? 5. Environment: Is there sufficient access to resources (equipment, facilities, etc.)? Does the scientific and technological environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Are the planned statistical and data management resources adequate? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be applied to ALL applications in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participations in the proposed research will be assessed. (See additional information and criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See additional information and Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the required five items described under Vertebrate Animals (section f of the Research Plan instructions) will be assessed. Human Subjects: 1. Protection of Human Subjects from Research Risks - for all studies involving human subjects. See instructions and "Guidance for Preparing the Human Subjects Research Section." If an exemption is claimed, is it appropriate for the work proposed? If no exemption is claimed, are the applicant's responses to the six required points appropriate? Are human subjects placed at risk by the proposed study? If so, are the risks reasonable in relation to the anticipated benefits to the subjects and others? Are the risks reasonable in relation to the importance of the knowledge that reasonably may be expected to be gained? Are the plans proposed for the protection of human subjects adequate? 2. Inclusion of Women Plan - for clinical research only. Does the applicant propose a plan for the inclusion of both genders that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? 3. Inclusion of Minorities Plan - for clinical research only. Does the applicant propose a plan for the inclusion of minorities that will provide their appropriate representation? Does the applicant provide appropriate justification when representation is limited or absent? Does the applicant propose appropriate and acceptable plans for recruitment/outreach and retention of study participants? 4. Inclusion of Children Plan- for all studies involving human subjects. Does the applicant describe an acceptable plan in which the representation of children of all ages (under the age of 21) is scientifically appropriate and recruitment/retention is addressed realistically? If not, does the applicant provide an appropriate justification for their exclusion? 5. Data and Safety Monitoring Plan for clinical trials only. Does the applicant describe a Data and Safety Monitoring Plan that defines the general structure of the monitoring entity and mechanisms for reporting Adverse Events to the NIH and the IRB? Animal Welfare: If vertebrate animals are involved, are adequate plans proposed for their care and use? Are the applicant's responses to the five required points appropriate? Will the procedures be limited to those that are unavoidable in the conduct of scientifically sound research? Biohazards: Is the use of materials or procedures that are potentially hazardous to research personnel and/or the environment proposed? Is the proposed protection adequate? ADDITIONAL CONSIDERATIONS: The following items may be also be considered by reviewers but will not be included in the determination of scientific merit. BUDGET: The reasonableness of the proposed budget may be considered. Is the percent effort listed for the PI appropriate for the work proposed? Is each budget category realistic and justified in terms of the aims and methods? PERIOD OF SUPPORT: The appropriateness of the requested period of support in relation to the proposed research. PHASE II APPLICATION REVIEW CRITERIA: In addition to the above criteria: 1. How well did the applicant demonstrate progress toward meeting the Phase I objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity? 2. Did the applicant submit a concise Commercialization Plan [formerly Product Development Plan] that adequately addresses the seven areas described in the Research Plan item J? 3. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? AMENDED APPLICATIONS: In addition to the above criteria, the following criteria will be applied to revised applications. 1. Are the responses to comments from the previous SRG review adequate? 2. Are the improvements in the revised application appropriate? PHASE I/PHASE II FAST-TRACK APPLICATION REVIEW CRITERIA: For Phase I/Phase II FAST-TRACK applications, the following criteria also will be applied. 1. Does the Phase I application specify clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II? 2. Did the applicant submit a concise Commercialization Plan [formerly Product Development Plan] that adequately addresses the seven areas described in the Research Plan, item J? 3. To what extent was the applicant able to obtain letters of interest, additional funding commitments, and/or resources from the private sector or non-SBIR/ STTR funding sources that would enhance the likelihood for commercialization? 4. Does the project carry a high degree of commercial potential, as described in the Commercialization Plan? Phase I and Phase II FAST-TRACK applications that satisfy all of the review criteria will receive a single rating. Failure to provide clear, measurable goals may be sufficient reason for the scientific review group to exclude the Phase II application from FAST-TRACK review. COMPETING CONTINUATION APPLICATIONS: In addition to the above criteria, the following criteria will be applied to competing continuation applications. 1. Does the activity as proposed address issues related to Federal regulatory approval processes? 2. What will be the effect of these studies on the concepts or methods that drive this field? AWARD CRITERIA Applications submitted in response to a PAR will compete for available funds with all other recommended SBIR and STTR applications. Portions of the SBIR and STTR allotments will not be designated for this initiative. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities For FAST-TRACK applications, the Phase II portion may not be funded until a Phase I final report and other documents necessary for continuation have been received and assessed by program staff that the Phase I milestones have been successfully achieved. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Dates: May 14, 2003 and November 13, 2003 Application Receipt Dates: June 11, 2003 and December 11, 2003 Council Review Dates: February 18, 2004 and June 8, 2004 Earliest Anticipated Award Date: April 1, 2004 and July 1, 2004 REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving clinical trials, including Phase I and Phase II trials, must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety-monitoring plan as part of the research application. See NIH Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I and II Trials" for additional information: http://grants.nih.gov/grants/guide/notice- files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: http://www.cancer.gov/clinical_trials/ INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_ amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research in now available online at: http://cme.nci.nih.gov/ PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PAR in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PAR is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.394 see http://www.cfda.gov/, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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